Resistance to existing antibiotics coupled with the decline in the development of new alternatives necessitates the search for agents to prevent and treat serious bacterial infections. Methicillin-Resistant Staphylococcus Aureus (MRSA) is the most widespread bacterial pathogen in the United States1 and in the developed world. MRSA causes a wide range of infections ranging from skin and soft tissue to more invasive forms, such as pneumonia, endocarditis, meningitis, bacteremia and sepsis. The increase in S. aureus infections has been associated with hospitalization, affecting preferentially immune compromised individuals. Recently, such infections also increasingly occur in the community in healthy individuals, such as athletes, students, prisoners, etc. These community-associated infections (CA-MRSA) are generally more virulent than hospital associated infections (HA-MRSA). Treatment of S. aureus infections is hampered by the steady increase of resistance against conventional antibiotics. Over two thirds of S. aureus infections are resistant to methicillin, a second-generation β-lactam antibiotic. Vancomycin, linezolid and daptomycin are the antibiotics of last resort against MRSA. Alarmingly, strains recently have emerged that are resistant to vancomycin. Therefore, the development of new therapeutic solutions against MRSA represents an urgent medical need.
Antivirulence agents present alternatives to conventional antibiotics. In contrast to antibiotics, antivirulence agents are not bactericidal, and generally are not even bacteriostatic. Their mechanism of action is based upon curtailing the pathogen's ability to elicit toxins against the host's immune system. An unimpaired immune system may be able to fight off the infection on its own. Alternatively, a boost in the form of a low-dose conventional antibiotic in combination with an antivirulence agent may become a successful strategy against more invasive infections. Antivirulence therapy offers the attractive prospect of bringing back conventional and affordable antibiotics into the clinic.